Methionine aminopeptidases as potential targets for treatment of gastrointestinal cancers and other tumours

Abstract

Methionine aminopeptidases (MetAP) are intracellular metalloproteins responsible for the removal of the initiator NH(2)-terminal methionine from newly synthesized proteins, thereby facilitating their intracellular translocation from the ribosome. Two types of MetAP enzymes, MetAP-1 (type-I) and MetAP-2 (type-II), which have a similar three-dimensional structure despite a low homology in their sequences, have been described. Since the discovery that fumagillin, an irreversible MetAP-2 inhibitor, prevents angiogenesis, different studies have been carried out to analyze the role of MetAP proteins as potential targets in cancer treatment. Data obtained indicate that anticancer effect of MetAP-2 inhibitors may be a result of the combined effect of MetAP-2 inhibition in endothelial cells (anti-angiogenesis) and in tumour cells directly. Moreover, it has been recently described that MetAP-1 has a potential role on cell division, and MetAP-1-specific inhibition is able to induce apoptosis in both HeLa and HT-1080 cell lines. A new subtype of MetAP-1, called MetAP-1D, has been found overexpressed in samples from colon cancer patients, its inhibition resulting in a decreased cell growth. Although molecular mechanisms of action of these proteins are largely unknown, a significant progress has been made to understand their structure-function relationships and their physiological roles. Their potential as promising targets in cancer treatment and in the development of new antitumour agents is analyzed focusing on MetAP irreversible inhibitors. The present review summarizes recent research data on different molecules able to induce MetAP inhibition in gastrointestinal cancers and other tumours.